This application responds to a Request for Applications from the NIMH to establish Research Units of Psychopharmacology and Psychosocial Interventions (RUPP-PI). The application builds on the expertise of our investigative group and our experience with multisite studies, especially NIH funded multisite psychopharmacological and psychosocial intervention studies. We have a track record of providing leadership and the capacity to function amiably and collegially in our collaborative efforts. The Scientific Aims of our research group are highly compatible with the spirit of the RFA for the RUPP-PI. Our goals are to develop and implement multisite: 1) efficacy studies that establish new evidence-based psychopharmacological and psychosocial treatments; 2) innovative efficacy studies that determine the optimal "dose" of treatments, optimal sequence of treatments, rational timing of discontinuation of treatments, and comparative treatment trials; 3) effectiveness studies that apply the results of efficacy studies in "real world" settings, such as schools, pediatric practices, and community mental health centers; 4) methods to effectively monitor long-term safety of psychotropic medications. The exemplar protocol contained in this proposal has unique public health significance, is feasible, inclusive, and designed to be implemented according to the highest ethical standards. It describes a 5-year multisite 3-arm, double blind, placebo substitution intervention to establish the optimal length of antidepressant treatment in children and adolescents with Major Depressive Disorder.